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[EN] Recent trends in waste management have initiated interest in recycled materials for sound absorption applications. The present paper studies the possibility of paper sludge to be recycled as material for sound absorption applications. Paper sludge (PS) is the water treatment waste, produced during paper production. Two different methods were studied to produce paper sludge and slaked lime composite acoustic panels for sound absorption applications at low and mid-frequencies. The sound absorption coefficient of paper sludge composite panels is measured in an impedance tube using the two-microphone method. The samples produced with different methods showed different behaviours of sound absorption. The primary method to produce showed acoustic asymmetry in the vertical direction of the samples, and it was considerably fragile as well. An improved method to produce PS composite panels was proposed in this paper. Using this method, homogenous and robust acoustic panels were obtained., The authors would like to kindly thank the technician Javier Zaragoza Dolz and Dr. Olga Kizinievi for their fruitful suggestions on this study. This research was financially supported by the Ministry of Science and Innovation and the European Union FEDER through Project PID2019-109175GB-C22

Executive SummaryThe EC Directive 2013/59/Euratom states in article 56 that exposures of target volumes in nuclear medicine treatments shall be individually planned and their delivery appropriately verified. The Directive also mentions that medical physics experts should always be appropriately involved in those treatments. Although it is obvious that, in nuclear medicine practice, every nuclear medicine physician and physicist should follow national rules and legislation, the EANM considered it necessary to provide guidance on how to interpret the Directive statements for nuclear medicine treatments.For this purpose, the EANM proposes to distinguish three levels in compliance to the optimization principle in the directive, inspired by the indication of levels in prescribing, recording and reporting of absorbed doses after radiotherapy defined by the International Commission on Radiation Units and Measurements (ICRU): Most nuclear medicine treatments currently applied in Europe are standardized. The minimum requirement for those treatments is ICRU level 1 (“activity-based prescription and patient-averaged dosimetry”), which is defined by administering the activity within 10% of the intended activity, typically according to the package insert or to the respective EANM guidelines, followed by verification of the therapy delivery, if applicable. Non-standardized treatments are essentially those in developmental phase or approved radiopharmaceuticals being used off-label with significantly (> 25% more than in the label) higher activities. These treatments should comply with ICRU level 2 (“activity-based prescription and patient-specific dosimetry”), which implies recording and reporting of the absorbed dose to organs at risk and optionally the absorbed dose to treatment regions. The EANM strongly encourages to foster research that eventually leads to treatment planning according to ICRU level 3 (“dosimetry-guided patient-specific prescription and verification”), whenever possible and relevant. Evidence for superiority of therapy prescription on basis of patient-specific dosimetry has not been obtained. However, the authors believe that a better understanding of therapy dosimetry, i.e. how much and where the energy is delivered, and radiobiology, i.e. radiation-related processes in tissues, are keys to the long-term improvement of our treatments.

Ethanol production from the steam-exploded mixture of 75% cotton gin waste and 25% recycled paper sludge in various conditions was investigated by semi-simultaneous saccharification and fermentation (SSSF) consisting of a pre-hydrolysis and a simultaneous saccharification and fermentation (SSF). Four cases were studied: 24-h pre-hydrolysis + 48-h SSF (SSSF 24), 12-h pre-hydrolysis + 60-h SSF (SSSF 12), 72-h SSF, and 48-h hydrolysis + 24-h fermentation (SHF). The ethanol concentration, yield, and productivity of SSSF 24 were higher than those of the other operations. A model of SSF was used to simulate the data for four components in SSF. The analysis of the reaction rates of cellobiose, glucose, cell, and ethanol using the model and the parameters from the experiments showed that there was a transition point of the rate-controlling step at which the cell growth control in the initial 2 h was changed to the cellobiose reaction control in later period during ethanol production of SSF from the mixture.

As part of an International Agency for Research on Cancer (IARC) international epidemiological study of workers in the pulp and paper industry, previously unpublished exposure measurements were assembled in a database. This article summarizes the results of 3,873 measurements carried out in the production departments of paper and paperboard mills and recycling plants in 12 countries. In the paper and paperboard mills, most of the agents were measured in the pulping and refining departments and in on-machine coating and winding of paper/paperboard. Exposures to asbestos, carbon monoxide, formaldehyde, fungal spores, bacteria, nitrogen dioxide, minerals dusts, paper dust, sulphuric acid and different solvents sometimes exceeded exposure limit values. In the re-pulping and de-inking departments of recycling plants high exposures to formaldehyde, fungal spores, bacteria and paper dust were observed. High exposures to asbestos, bioaerosols, carbon monoxide and paper dust were found in many departments; ammonia, formaldehyde, mineral and paper dust and solvents were found in coating machines; and diphenyl and polychlorobiphenyls (PCBs) were found in some special circumstances. Measurements in the newsprint and uncoated paper machine departments revealed only a few elevated exposures. In nearly all departments, measurements of epichlorohydrin, PCBs, sulphur dioxide, hydrogen sulphide and mercaptans tended to be low, often even below their detection limits. In spite of some uncertainties in the measurement data, the study provides new insights into the level and variation of occupational exposures of production workers in the paper and paperboard industry. © Springer-Verlag 2004.

Objectives EQ-5D-Y-3L health states are valued by adults taking the perspective of a 10-year-old child. Compared to valuation of adult EQ-5D instruments, this entails two changes to the perspective: (i) child health states are valued instead of adult health states and: (ii) health states are valued for someone else instead of for oneself. Although earlier work has shown that these combined changes yield different values for child and adult health states that are otherwise equal, it currently remains unclear why. Hence, we aimed to disentangle the effects of both changes. Methods A sample of 205 students (mean age: 19.48) was surveyed. Each respondent completed visual analogue scale (VAS) and time trade-off (TTO) tasks for five EQ-5D-Y-3L states, using four randomly ordered perspectives: (i) self-adult (themselves), (ii) other-adult (someone their age), (iii) self-child (themselves as a 10-year-old), (iv) other-child (a child of 10 years old). We compared how each perspective impacted outcomes, precision and quality of EQ-5D-Y-3L valuation. Results Overall, differences between perspectives were consistent, with their direction being dependent on the health states and respondents. For VAS, the effect on outcomes of valuation depended on severity, but variance was higher in valuation with child perspectives. For TTO, we observed that EQ-5D-Y-3L states valued on behalf of others (i.e., children or adults) received higher valuations, but lower variances. Conclusion The use of a different perspective appears to yield systematic differences in EQ-5D-Y-3L valuation, with considerable heterogeneity between health states and respondents. This may explain mixed findings in earlier work.

Purpose Over 20 years ago the term non-specific low back pain became popular to convey the limitations of our knowledge of the pathological source of most people's low back pain. Knowledge of underlying pathology has advanced little since then, despite limited improvements in outcomes for patients with low back pain. Methods This paper discusses potential misunderstandings related to diagnostic studies in the field of low back pain and argues that future diagnostic studies should include and investigate pathological sources of low back pain. Results Six potential misunderstandings are discussed. (1) Until diagnosis is shown to improve outcomes it is not worth investigating; (2) without a gold standard it is not possible to investigate diagnosis of low back pain; (3) the presence of pathology in some people without low back pain means it is not important; (4) dismissal of the ability to diagnose low back pain in clinical guidelines is supported by the same level of evidence as recommendations for therapy; (5) suggesting use of a diagnostic test in research is misinterpreted as endorsing its use in current clinical practice; (6) we seem to have forgotten the 'bio' in biopsychosocial low back pain. Conclusions We believe the misunderstandings presented in this paper partly explain the lack of investigation into pathology as an important component of the low back pain experience. A better understanding of the biological component of low back pain in relation, and in addition, to psychosocial factors is important for a more rational approach to management of low back pain.

The syndromic primary immunodeficiencies are disorders in which not only the immune system but also other organ systems are affected. Other features most commonly involve the ectodermal, skeletal, nervous, and gastrointestinal systems. Key in identifying syndromic immunodeficiencies is the awareness that increased susceptibility to infections or immune dysregulation in a patient known to have other symptoms or special features may hint at an underlying genetic syndrome. Because the extraimmune clinical features can be highly variable, it is more difficult establishing the correct diagnosis. Nevertheless, correct diagnosis at an early age is important because of the possible treatment options. Therefore, diagnostic work-up is best performed in a center with extensive expertise in this field, having immunologists and clinical geneticists, as well as adequate support from a specialized laboratory at hand. This paper provides the general pediatrician with the main clinical features that are crucial for the recognition of these syndromes.

The syndromic primary immunodeficiencies are disorders in which not only the immune system but also other organ systems are affected. Other features most commonly involve the ectodermal, skeletal, nervous, and gastrointestinal systems. Key in identifying syndromic immunodeficiencies is the awareness that increased susceptibility to infections or immune dysregulation in a patient known to have other symptoms or special features may hint at an underlying genetic syndrome. Because the extraimmune clinical features can be highly variable, it is more difficult establishing the correct diagnosis. Nevertheless, correct diagnosis at an early age is important because of the possible treatment options. Therefore, diagnostic work-up is best performed in a center with extensive expertise in this field, having immunologists and clinical geneticists, as well as adequate support from a specialized laboratory at hand. This paper provides the general pediatrician with the main clinical features that are crucial for the recognition of these syndromes.

We have been glad to see that our paper (Scherrer and Jost 2007) solicited such insightful or supportive commentaries as those of Noble, of Gros, of Prohaska and Stadler, of Forsdyke, and Billeter, as well as the alternative proposal of Stadler et al., and we hope that this will trigger further conceptual discussions about the definition of the gene and inspire further research about programs of gene expression, in the light of recent advances in molecular biology and bioinformatics (Billeter 2009; Forsdyke 2009; Gros 2009; Noble 2009; Prohaska and Stadler 2008; Stadler et al. 2009). The commentaries raise some important issues. We agree with some of them, but disagree with others, whereas still others reflect terminological decisions that could be taken so or otherwise. In the sequel, we shall try to address these issues in a systematic manner and motivate the terminological decisions that we have taken. This will also give us the opportunity to emphasize some points that were not explicitly laid out in our original paper.

Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.

The future of medicine lies in early diagnosis and individually tailored treatments, a concept that has been designated 'personalised medicine' (PM), i.e. delivering the right treatment to the right patient at the right time. However, the value of medical imaging in PM is frequently underestimated, as many policy makers forget the all-important right location in the PM paradigm. Medical imaging has always been personalised as it provides individual assessment of the location and extent of an abnormality, and in the future it will prove fundamental to almost all aspects of PM. Stratification based on imaging biomarkers can help identify individuals suited for preventive intervention and can improve disease staging. In vivo visualisation of locoregional physiological, biochemical and biological processes using molecular imaging can detect diseases in pre-symptomatic phases or facilitate individualised drug delivery. Furthermore, imaging is essential to patient-tailored therapy planning, therapy monitoring and follow-up of disease progression, as well as targeting non-invasive or minimally invasive treatments, especially with the rise of theranostics. For PM to reach its full potential, medical imaging must be an integral part. Radiologists need to be prepared for this new paradigm as it will mean changes in training, in research and in clinical practice.

The Papers Presented at the Annual Meetings of the Knee Society Symposium includes selected papers read at the 2007 Annual Interim Meeting of the Knee Society held in Sienna, Italy in September 2007, and the 2008 Open Scientific Meeting of the Knee Society, held in San Francisco in March 2008. The wide range and high quality of the scientific material presented here is a credit to the excellent work of the Knee Society education committee and particularly to its Program Chair, Gil Scuderi, MD. Each of these papers is focused, concise and highly readable, which is a credit to the outstanding work of the staff at CORR in providing clear and consistent guidelines for each of the authors whose work was accepted for publication. The 2008 Ranawat Award was authored by Dr. Patricia Franklin and colleagues for their work on patient-specific attributes that affect the functional outcome after total knee replacement. While considerable interest in patient outcomes research has been present for some time now, we are still uncovering the hidden power, and the hidden pitfalls, of such evaluation tools in orthopaedics. Dr. Franklin and colleagues effectively demonstrate the substantial influence of specific patient characteristics in determining the ultimate functional outcome after knee replacement. These data are useful for surgeons and patients alike as part of the preoperative discussion so that expectations can be managed more appropriately. Further, this paper provides some insight into additional strategies that might be employed prior to knee replacement to affect some patient attributes that adversely impact outcome. The 2008 Coventry Award paper was authored by D’Lima, Colwell, and colleagues from the Scripps Clinic for their innovative report that directly measured the in vivo forces that the knee experiences after total knee arthroplasty. In an outstanding collaboration between basic science researchers, engineers, and clinicians, Dr. Colwell’s group designed and implanted in three patients an instrumented tibial component that allowed the direct measurement of both knee forces and moments in vivo. These results begin to give us a true glimpse of the forces that are seen by total knee bearing surfaces and fixation interfaces thus providing us with a more scientific approach to what have otherwise been empiric recommendations regarding physical activities after total knee arthroplasty. The 2008 John Insall Award paper was authored by Dr. Steven MacDonald and colleagues from London, Ontario and addressed the specific impact of gender on the clinical outcome after total knee arthroplasty. The introduction into the marketplace of so-called gender-specific total knee components has been met with a competing mix of interest and skepticism among surgeons, while among patients curiosity might be the most appropriate descriptor. This scientific work again highlights the powerful relationship between preoperative variables and postoperative outcomes. These authors rightly highlight the importance of focusing on the change or improvement in preoperative to postoperative outcomes measures and balance that against the absolute scores. Female gender was associated with lower preoperative scores with these outcomes tools so perhaps it is not surprising some of the postoperative scores remain lower than those observed in males. The change or improvement from preoperative to postoperative, however, appears to be similar between males and females after total knee arthroplasty. The remaining papers in this symposium are grouped to include new information regarding total knee surgical technique, gender-related issues in technique and outcome, computer navigation, patellar resurfacing, total knee materials and design issues and revision total knee concerns. As surgeons we have specific interest in improving our intraoperative skills. In this symposium there is information on a method to determine rotational position of total knee components, data on the impact of a ligament balancing technique on the rate of lateral retinacular release, and the introduction of an extramedullary femoral referencing system to facilitate less invasive surgery. Gender-related issues are addressed in a series of papers that look at both documenting physical measurement differences in knee anatomy and then measuring outcomes differences. While little doubt exists that gender-associated differences can be measured, what remains to be determined is the clinical importance of such findings, and in that area we collectively still have work to do. While it appears that the initial wave of enthusiasm for computer navigation in total knee arthroplasty has crested, we are now at a point where more definitive scientific data are emerging regarding the benefits and drawbacks to this particular technology. Two of the implicit promises of computer navigation have been that it may make the occasional knee surgeon more like the expert surgeon, and that a navigation system can be the eye that facilitates accurate minimally invasive surgery. In this symposium there are scientific data that cast some doubt on promise number two, and all of us in the scientific community continue to look for evidence that navigation is reproducibly accurate when used by the occasional knee surgeon. The added costs of this technology is an issue yet to be addressed. Revision TKA is an area of ascending importance as the demographics of our population point to a growing need in this area. In this Symposium there are useful data on the outcomes differences between primary and revision TKA, comparative data on in-hospital complications between primary and revision TKA, isolated patellar revision, patellar bone loss problems and the use of stems in conjunction with constrained condylar knee designs. The Knee Society remains committed to advancing scientific knowledge and educating clinicians worldwide regarding surgery of the knee. We hope that our readers find this Symposium to be intellectually rigorous and clinically useful.

Fractures are reported to be the second most common findings in child abuse, after skin lesions such as bruises and contusions. This makes careful interpretation of childhood fractures in relation to the provided clinical history important. In this literature review, we address imaging techniques and the prevailing protocols as well as fractures, frequently seen in child abuse, and the differential diagnosis of these fractures. The use of a standardised protocol in radiological imaging is stressed, as adherence to the international guidelines has been consistently poor. As fractures are a relatively common finding in childhood and interpretation is sometimes difficult, involvement of a paediatric radiologist is important if not essential. Adherence to international guidelines necessitates review by experts and is therefore mandatory. As in all clinical differential diagnoses, liaison between paediatricians and paediatric radiologists in order to obtain additional clinical information or even better having joint review of radiological studies will improve diagnostic accuracy. It is fundamental to keep in mind that the diagnosis of child abuse can never be solely based on radiological imaging but always on a combination of clinical, investigative and social findings. The quality and interpretation, preferably by a paediatric radiologist, of radiographs is essential in reaching a correct diagnosis in cases of suspected child abuse.

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies and are characterized by a defect in the production of normal amounts of antigen-specific antibodies. PADs represent a heterogeneous spectrum of conditions, ranging from often asymptomatic selective IgA and IgG subclass deficiencies to the severe congenital agammaglobulinemias, in which the antibody production of all immunoglobulin isotypes is severely decreased. Apart from recurrent respiratory tract infections, PADs are associated with a wide range of other clinical complications. This review will describe the pathophysiology, diagnosis, and treatment of the different PADs.

Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency characterized by absence of functional T lymphocytes. It is a paediatric emergency, which is life-threatening when recognized too late. The clinical presentation varies from the classical form of SCID through atypical SCID to Omenn syndrome. In addition, there is a considerable immunological variation, which can hamper the diagnosis. In this educational review, we describe the immunopathological background, clinical presentations and diagnostic process of SCID, as well as the therapeutic possibilities.

The purpose and focus of the Musculoskeletal Tumor Society is stated on the organization’s website. “The mission of the Musculoskeletal Tumor Society is to advance the science of orthopaedic oncology and to promote high standards of patient care. It does this through excellence in education and research” [1]. The 2008 MSTS meeting in Phoenix, AZ, November 6–8, 2008, and hence this symposium, follows part of the prescription, providing an excellent forum for education. The second portion of the mission statement encourages advancing orthopaedic oncology through research. The organization has enjoyed limited success in conducting or promoting research despite valiant efforts by the leaders of the Research Committee. Why? Answers come from the membership, the discipline, and the organization. The membership of the MSTS has changed dramatically over the years. The original “Piranha Club” had 18 domestic orthopaedic surgeons, of whom only one remains actively practicing surgical oncology. The roster has ballooned to over 220 members, including Candidate, Affiliate, and Emeritus Members. While this reflects successful maturation of orthopaedic oncology, it has a dilutive effect on research and possibly even clinical progress. Case volume is correlated with outcome in all other cancer systems studied to date, for disease of organs ranging from prostate to pancreas. Why shouldn’t it also be true for bone and soft tissue sarcomas? As knowledge and training disseminate, experience per surgeon inevitably declines. Smaller case loads prevent concentrated expertise. Paradoxically, the numerical expansion of our membership may have improved our ability to deliver more convenient, good quality care to more people, but it may prevent us from making substantive advances in the field. Single centers usually lack the volume to ask or answer important questions. Collaboration is essential to maintain patient numbers required to study rare diseases. Standardization of treatment protocols is essential if the cases from different centers may be combined. This requires strong-willed commitment on the part of musculoskeletal oncologists to suppress some of their individuality and cooperate. This is necessary to advance the discipline and improve patient care. Large cooperative groups (eg, Children’s Oncology Group or COG, the Southwest Oncology Group or SWOG) have failed due to their cumbersome structure and an inability to channel resources to orthopaedic problems. The greatest success has been in ad hoc collaborations such as that coordinated by the MSTS to review the outcome of patients treated by limb salvage or amputation for distal femoral osteosarcoma [2], or the Toronto Group’s prospective evaluation of prognostic genetic markers (p53 and RB) in osteosarcoma patients from six centers [3]. This symposium includes a variety of novel and informative clinical papers dealing with resection and reconstruction techniques. However, most are single center studies that should be viewed as hypothesis generating ideas. They require confirmation in larger trials involving other centers to show the results can be generalized. The levels of evidence are typically IV. There is also a deficiency in basic and translational research needed to advance the field. Clearly, more effort needs to be expended to improve the quality and generalizability of our research. Investigators and reviewers need to support cluster- and association-based comparative research efforts, clinical trials, and basic investigations. There are national initiatives in this direction. Responding to the challenge proposed by the American Academy of Orthopaedic Surgeons, the Musculoskeletal Tumor Society is trying to develop evidence-based assessments of practice. This symposium includes the Society’s first effort along those lines, summarizing the best available opinion regarding the biopsy of musculoskeletal tumors. More recently, the AAOS/ORS/NIH sponsored a workshop in Albuquerque to define the research agenda for prospective outcome studies in each orthopaedic subspecialty. Two tumor projects made the final cut of recommendations. The first was a prospective study of proximal femoral metastases, comparing internal fixation (rodding) with joint arthroplasty. The second was a long-term followup of reconstructions performed for patients randomized to receive, or not receive, muramyl tripeptide phosphoethanolamine (MTP-PE) in the national Intergroup-133 study. These projects should receive the support of the oncology community, and would be good topics on which the MSTS could focus and include in future CORR Symposia.

AAPS-FDA workshop white paper : Microdialysis principles, application, and regulatory perspectives report from the joint AAPS-FDA workshop, November 4-5, 2005, Nashville, TN

Five years ago our department migrated from a film-based imaging environment to a PACS-based environment. We discovered that our reliance on paper tracking forms for clinical history and dictation information was hindering our practice. Integrating dictation with PACS was one of three key components we needed to free ourselves from the tyranny of paper, the other two being an online worklist and an online patient history. We discuss our evolution to a (mostly) paperless reading room environment, our implementation, general performance, and future development plans, focusing on integrated dictation.

The First Society for Computer Applications in Radiology (SCAR) Transforming the Radiological Interpretation Process (TRIP™) Conference and Workshop, “Transforming Medical Imaging” was held on January 31–February 1, 2005 in Bethesda, MD. Representatives from all areas of medical and scientific imaging—academia, research, industry, and government agencies—joined together to discuss the future of medical imaging and potential new ways to manage the explosion in numbers, size, and complexity of images generated by today's continually advancing imaging technologies. The two-day conference included plenary, scientific poster, and breakout sessions covering six major research areas related to TRIP™. These topic areas included human perception, image processing and computer-aided detection, data visualization, image set navigation and usability, databases and systems integration, and methodology evaluation and performance validation. The plenary presentations provided a general status review of each broad research field to use as a starting point for discussion in the breakout sessions, with emphasis on specific topics requiring further study. The goals for the breakout sessions were to define specific research questions in each topic area, to list the impediments to carrying out research in these fields, to suggest possible solutions and near- and distant-future directions for each general topic, and to report back to the general session. The scientific poster session provided another mechanism for presenting and discussing TRIP™-related research. This report summarizes each plenary and breakout session, and describes the group recommendations as to the issues facing the field, major impediments to progress, and the outlook for radiology in the short and long term. The conference helped refine the definition of the SCAR TRIP™ Initiative and the problems facing radiology with respect to the dramatic growth in medical imaging data, and it underscored a present and future need for the support of interdisciplinary translational research in radiology bridging bench-to-bedside. SCAR will continue to fund research grants exploring TRIP™ solutions. In addition, the organization proposes providing an infrastructure to foster collaborative research partnerships between SCAR corporate and academic members in the form of a TRIP™ Imaging Informatics Network (TRIPI2N).

What is the largest cube or sphere that a given rectangular piece of paper can wrap? This natural problem, which has plagued gift-wrappers everywhere, remains very much unsolved. Here we introduce new upper and lower bounds and consolidate previous results. Though these bounds rarely match, our results significantly reduce the gap.

Objectives To compare the cost-effectiveness of first-line gefitinib, erlotinib, afatinib, and osimertinib in patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. Methods A systematic review and network meta-analysis (NMA) were conducted to compare the relative efficacy of gefitinib, erlotinib, afatinib, and osimertinib in EGFR-mutated NSCLC. To assess the cost-effectiveness of these treatments, a Markov model was developed from Dutch societal perspective. The model was based on the clinical studies included in the NMA. Incremental costs per life-year (LY) and per quality-adjusted life-year (QALY) gained were estimated. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Results Total discounted per patient costs for gefitinib, erlotinib, afatinib, and osimertinib were €65,889, €64,035, €69,418, and €131,997, and mean QALYs were 1.36, 1.39, 1.52, and 2.01 per patient, respectively. Erlotinib dominated gefitinib. Afatinib versus erlotinib yielded incremental costs of €27,058/LY and €41,504/QALY gained. Osimertinib resulted in €91,726/LY and €128,343/QALY gained compared to afatinib. PSA showed that gefitinib, erlotinib, afatinib, and osimertinib had 13%, 19%, 43%, and 26% probability to be cost-effective at a threshold of €80,000/QALY. A price reduction of osimertinib of 30% is required for osimertinib to be cost-effective at a threshold of €80,000/QALY. Conclusions Osimertinib has a better effectiveness compared to all other TKIs. However, at a Dutch threshold of €80,000/QALY, osimertinib appears not to be cost-effective.

Background Several multi-attribute utility instruments (MAUIs) are available from which utilities can be derived for use in cost-utility analysis (CUA). This study provides a review of recommendations from national health technology assessment (HTA) agencies regarding the choice of MAUIs. Methods A list was compiled of HTA agencies that provide or refer to published official pharmacoeconomic (PE) guidelines for pricing, reimbursement or market access. The guidelines were reviewed for recommendations on the indirect calculation of utilities and categorized as: a preference for a specific MAUI; providing no MAUI preference, but providing examples of suitable MAUIs and/or recommending the use of national value sets; and recommending CUA, but not providing examples of MAUIs. Results Thirty-four PE guidelines were included for review. MAUIs named for use in CUA: EQ-5D (n = 29 guidelines), the SF-6D (n = 11), HUI (n = 10), QWB (n = 3), AQoL (n = 2), CHU9D (n = 1). EQ-5D was a preferred MAUI in 15 guidelines. Alongside the EQ-5D, the HUI was a preferred MAUI in one guideline, with DALY disability weights mentioned in another. Fourteen guidelines expressed no preference for a specific MAUI, but provided examples: EQ-5D (n = 14), SF-6D (n = 11), HUI (n = 9), QWB (n = 3), AQoL (n = 2), CHU9D (n = 1). Of those that did not specify a particular MAUI, 12 preferred calculating utilities using national preference weights. Conclusions The EQ-5D, HUI, and SF-6D were the three MAUIs most frequently mentioned in guidelines. The most commonly cited MAUI (in 85% of PE guidelines) was EQ-5D, either as a preferred MAUI or as an example of a suitable MAUI for use in CUA in HTA.

Objectives Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions. Methods Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact. Results Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (− 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2–€12.8 million (TAVI) for TEHV substitution rates of 25–100%. Conclusions Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.

Background Multiparametric MRI (mpMRI) became recognised in investigating those with suspected prostate cancer between 2010 and 2012; in the USA, the preventative task force moratorium on PSA screening was a strong catalyst. In a few short years, it has been adopted into daily urological and oncological practice. The pace of clinical uptake, born along by countless papers proclaiming high accuracy in detecting clinically significant prostate cancer, has sparked much debate about the timing of mpMRI within the traditional biopsy-driven clinical pathways. There are strongly held opposing views on using mpMRI as a triage test regarding the need for biopsy and/or guiding the biopsy pattern. Objective To review the evidence base and present a position paper on the role of mpMRI in the diagnosis and management of prostate cancer. Methods A subgroup of experts from the ESUR Prostate MRI Working Group conducted literature review and face to face and electronic exchanges to draw up a position statement. Results This paper considers diagnostic strategies for clinically significant prostate cancer; current national and international guidance; the impact of pre-biopsy mpMRI in detection of clinically significant and clinically insignificant neoplasms; the impact of pre-biopsy mpMRI on biopsy strategies and targeting; the notion of mpMRI within a wider risk evaluation on a patient by patient basis; the problems that beset mpMRI including inter-observer variability. Conclusions The paper concludes with a set of suggestions for using mpMRI to influence who to biopsy and who not to biopsy at diagnosis. Key Points • Adopt mpMRI as the first, and primary, investigation in the workup of men with suspected prostate cancer. • PI-RADS assessment categories 1 and 2 have a high negative predictive value in excluding significant disease, and systematic biopsy may be postponed, especially in men with low-risk of disease following additional risk stratification. • PI-RADS assessment category lesions 4 and 5 should be targeted; PI-RADS assessment category lesion 3 may be biopsied as a target, as part of systematic biopsies or may be observed depending on risk stratification. Electronic supplementary material The online version of this article (10.1007/s00330-019-06166-z) contains supplementary material, which is available to authorized users.

Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.

Custom-made mandibular advancement devices are an effective treatment option for snoring, upper airway resistance syndrome, and obstructive sleep apnea (OSA). Evidence-based data indicates their efficacy, and international sleep societies recommend oral appliance (OA) therapy for patients with sleep-related breathing disorders. The following position paper by the German Society of Dental Sleep Medicine (DGZS) is to guide the interdisciplinary team (sleep physician and sleep disorder dentist) in detail when to prescribe oral appliances. This position paper supports the responsible use of OA as an effective treatment option for patients with sleep-related breathing disorders. The paper advises of proper indication regarding OSA severity, body mass index (BMI), and dentition. It emphasizes the interdisciplinary approach of oral appliance therapy and suggests treatment under the guidance of dentists trained in dental sleep medicine.

I have recently returned from the Society for Imaging Informatics in Medicine (SIIM) 2012 Annual Meeting and was reading Dr. Bruce Reiner and Matthew McKinley’s (“Reiner and McKinley’s”) excellent paper on the plane ride home, entitled “Application of Innovation Economics to Medical Imaging and Information System Technologies”, JDI, June 2012. The paper is courageous and shines the light on an incredibly important topic for SIIM, our industry and the healthcare system that we all collectively serve. I was struck by many statements in the paper, and would like to share my thoughts. First, these are the extracted areas that most resonated

We propose a methodology to identify and resolve proteinrelated abbreviations found in the full texts of scientific papers, as part of a semi-automatic process implemented in our PRAISED framework. The identification of biological acronyms is carried out via an effective syntactical approach, by taking advantage of lexical clues and using mostly domain-independent metrics, resulting in considerably high levels of recall as well as extremely low execution time. The subsequent abbreviation resolution uses both syntactical and semantic criteria in order to match an abbreviation with its potential explanation, as discovered among a number of contiguous words proportional to the abbreviation's length. We have tested our system against the Medstract Gold Standard corpus and a relevant set of manually annotated PubMed papers, obtaining significant results and high performance levels, while at the same time allowing for great customization, lightness and scalability.

This study analyzes the relation between attention-deficit hyperactivity disorder (ADHD) and later-life labor market outcomes in the United States and whether these relationships are mediated by educational attainment. To overcome endogeneity concerns in the estimation of these relationships, we exploit the polygenic risk score (PRS) for ADHD in a cohort where the diagnosis of and treatment for ADHD were generally not available. We find that an increase in the PRS for ADHD reduces the likelihood of employment, individual income, and household wealth. Moreover, it increases the likelihood of receiving social security disability benefits, unemployment or worker compensation, and other governmental transfers. We provide evidence that educational attainment mediates these relationships to a considerable extent (14-58%).

Background We aimed to investigate the burden of informal care in Hungary (HU), Poland (PL) and Slovenia (SI). Methods A cross-sectional online survey was performed involving representative samples of 1000 respondents per country. Caregiving situations were explored; health status of informal caregivers/care recipients and care-related quality of life were assessed using the EQ-5D-5L and CarerQol-7D. Results The proportion of caregivers was (HU/PL/SI) 14.9, 15.0 and 9.6%, respectively. Their mean age was 56.1, 45.6 and 48.0, and the average time spent on informal care was 27.6, 35.5 and 28.8 h/week. Chronic care was dominant (> 1 year: 78.5%, 72.0%, 74.0%) and care recipients were mainly (own/in-law) parents. Average EQ-5D-5L scores of care recipients were 0.53, 0.49 and 0.52. For Poland and Slovenia, EQ-5D-5L scores of informal care providers were signifcantly lower than of other respondents. Average CarerQol-7D scores were (HU/PL/SI) 76.0, 69.6 and 70.9, and CarerQol-VAS was 6.8, 6.4 and 6.6, respectively. Overall, 89, 87, and 84% of caregivers felt some or a lot fulflment related to caring. Problems with combining tasks with daily activities were most important in Hungary and Slovenia. Women had a higher probability of being a caregiver in Hungary. CarerQol-7D scores were signifcantly associated with caregivers’ EQ-5D-5L scores. In Hungary and Poland, living in a larger household was positively, while caring for patients with mental health problems was negatively associated with CarerQol-7D scores. Conclusions These frst results from the Central and Eastern European region using preference-based measures for the evaluation of informal care can serve as a valuable input for health economic analyses.

Lecture Notes in Computer Science

The authors present a case of a spondylolisthesis with obvious foraminal stenosis on both sides as shown on the preoperative MRI. A proper operative technique in this case would include a restoration of disc height and the (partial) reduction of the slip. This technique would widen both foramina and no complication like opposite nerve root compression would occur. If reduction or disc height restoration cannot be achieved, decompression of both foramina should be performed. In mild cases a simple posterior distraction may be enough. In their paper the authors agree to this point as they write “decompression of the opposite side has not been judged necessary in the past as it has been commonly assumed that the TLIF spacer increases the disc space height and the foraminal height in the opposite foramen of the TLIF approach.” However, it seems that in the current case the authors failed to achieve restoration of disc height. Figure 7 shows differences between the preoperative and the postoperative CT scan of 1 mm (4 vs. 5 mm) and 1.5 mm (6.5 vs. 8 mm), respectively. The same is true for the “decrease” of foraminal height of 2 mm. I think that these measurements are not reliable since there is no calibration and no matching between the slices. Hence no obvious increase in disc height or decrease in foraminal height can be measured accurately. Anyway, the clinical significance of 1 or 2 mm of reduced foraminal height, if really present, seems to be questionable.

Despite the increasing availability of various forms of digital maps and guides, paper still prevails as the main information medium used by tourists during city visits. The authors describe how recent technologies for digitally augmented paper maps can be used to develop interactive paper maps that provide value-added services for tourists through digital overlays. An initial investigation into the use of these maps to support visitors to the Edinburgh festivals is also presented.

The work, "Ricardo M. The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union. Int Orthop. 2006 Apr;30(2):123–127", published by the prestigious journal International Orthopaedics, contains some misprints. In the paper it is reported that the ultrasound intensity emitted by the equipment employed in the study, a Theramed 101B, was 30 mW/cm2. Actually, the reported intensity should have been 50mW/cm2. The error could have come about since initially in the Department of Orthopedics and Traumatology of the Manuel Fajardo Teaching Hospital, a preliminary study was conducted for the stimulation of bone repair that indeed used 30mW/cm2. The first results of this preliminary study were published in the following reference, "O. Rodriguez, R. Monreal. Acceleration of Osseous Fracture Repair by Low-intensity Pulsed Ultrasound Therapy: A Preliminary Study", Proceedings of the II Latin-American Congress on Biomedical Engineering (ISBN 959-7132-57-5), Havana, Cuba, Cod. 265, (2001). Nevertheless after that preliminary study and since the beginning of 2000, the Theramed 101B equipment was modified for an emmision of 50 mW/cm2. Therefore, the year for the beginning of the study described by author should be 2000 and not 1999, and the reported intensity must be 50 mW/cm2, and not 30 mW/cm2. Sincerely yours, Orlando R. Rodriguez Rua (MD), Researcher of the “Instituto de Cibernetica, Matematica y Fisica”, La Habana Cuba. Chief of the project PRI/1/1 of the “Agencia Cubana de Energia Nuclear y Tecnologias de Avanzadas” under which the Theramed 101B was Developer with the collaboration of the “Departamento de Ingenieria Electrica y Electronica, Instituto Tecnologico y de Estudios Superiores de Monterrey, Campus Estado de Mexico, Mexico” and the “Seccion de Bioelectronica, Departamento de Ingenieria Electrica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico DF, Mexico”.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation OnBehalf Swiss-AF Investigators Background Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients. Methods Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they presented in AF ("AF group") or in sinus rhythm ("SR group") on a baseline 5-minute ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), the root mean square of successive differences (RMSSD) and the standard deviation of the normal-to-normal intervals (SDNN)) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function. Results 1,685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. The MoCA score was 24.5 ± 3.2 in the AF group (n = 710 patients) and 25.4 ± 3.2 in the SR group (n = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group (β=0.049; 95% confidence interval (CI): 0.016 to 0.081; p = 0.003) and in the AF group (β=0.068; 95% CI: 0.020 to 0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β=-0.008; 95% CI: -0.014 to -0.002; p = 0.014 ). Other parameters of CAF were not associated with cognition. Conclusion Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Elderly AF patients with impaired HRVI might undergo cognitive testing in order to screen for cognitive impairment.

AS AN EARLY PICTURE ARCHIVING AND COMMUNICATION SYSTEM (PACS) adopter, I am often asked about “the most important lesson that I’ve learned about filmless radiology.” Although we have learned many things during the past decade, the most important lesson has undoubtedly been that the purchase of a PACS provides an opportunity to re-engineer and streamline the inefficient manual workflow found in most conventional imaging departments. In my experience, many imaging departments have used PACS as an electronic substitute for film, completely emulating all aspects of a conventional department. Such departments continue to push individual studies from a specific acquisition device (such as a CT scanner) to a specific workstation in a manner similar to hanging films from that modality on a specific film alternator. They continue to enter patient information either electronically or on paper multiple times on multiple information systems in a manner analogous to paper and index cards, rather than having these systems communicate with each other. It is therefore not surprising that there have been mixed results with regard to the impact of PACS on departmental productivity and cost savings. It has been my experience that departments that have concentrated on redesign of workflow using integrated systems that communicate with each other have been able to achieve the greatest gains in savings and efficiency. In 1991, when we purchased our PACS for the Baltimore VA Medical Center, we were required to create custom interfaces for each of these information systems in order to achieve interoperability. Today, customers can take advantage of the Integrating the Healthcare Enterprise (IHE) effort to minimize the need to reinvent this wheel and to optimize departmental and/or hospital workflow for imaging. This paper discusses our analysis which compared our workflow processes before and after implementation of an enterprise-wide PACS.

OUR RESEARCH APPROACH to the development of a picture archiving and communication system (PACS) has been at the system level. While component technology was developed by various investigators, we felt that our unique role was to look at the PACS from the perspective of network and clinical operations as well as the management of insertion of technology into a complex environment. One of the first questions we tried to address was, “How should one describe PACS?” The paper reprinted here was an early attempt to describe PACS at an operational level without being limited to specific component technology, as we knew the technology would eventually change. This approach as laid the foundation for the performance specifications of the Medical Diagnostic Imaging System that the Department of Defense adopted in the 1990s. During that decade many new efforts were directed toward developing quantitative requirements for the PACS performance, especially to meet the needs of radiologists. Whereas workstation performance and network topologies were topics of intense discussion and development in various quarters, our focus remained on the system level performance and technology deployment. Today PACS is a mature technology. It is difficult to know if any aspects of PACS development influenced the advances in generic computer and information technology. It is reasonable to assume, however, that the PACS initiative has a significant impact on advancing imaging, image processing and image processing technologies. Certainly the PACS efforts in the radiology community have laid the foundation for filmless electronic hospitals and telemedicine. Many major technical issues have been resolved, but as applications expand and the landscape of usage changes, new issues arise. The questions of network topology, workstation performance, image quality on the electronic displays, digital radiography, and clinical acceptance are no longer challenges for PACS today. But the integration of PACS with the radiology information system and other enterprise-wide information and imaging systems continues to pose implementation difficulties. Network security, patient privacy, and health information assurance are a few of the new requirements that the PACS community must address. Through participation in the evolution of PACS, we have experienced firsthand the old lessons associated with the adoption of new technology. This process must begin with proof of the merit of the technology; in addition it requires overcoming entrenched habits and self-interest associated with preserving old technology and old work rules. For PACS, the process of maturation has taken more than 10 years. It was successful because the technology solved difficult problems of managing large amount of complex data for many different stakeholders. The next challenges may be the development of new research programs and patient care capabilities by accessing the vast image databases that are accumulating at PACS hospitals.

IT IS ILLUMINATING and perhaps a little humbling to review a paper written over 15 years ago and compare it to the state-of-the-art in PACS today. Clearly, there have been astounding improvements in the core technology: increased processing power, higher communications bandwidth, cost-effective storage capacity, and superb display technologies. However, the authors’ view (in 1987) that the industry (vendors and customers) needs to focus more on software and systems issues still rings true. Standardization of hardware and software components has come a long way with the digital imaging and communications in medicine (DICOM) and Integrating the Healthcare Enterprise (IHE) standards; without these yeoman efforts, PACS would still be in the dark ages. Also, PACS appears to have “graduated” from being a departmental solution to becoming more and more integrated into the mainstream clinical information systems from information technology providers. Despite these great achievements, I think the industry needs to invest more thought and effort into unleashing the power of PACS with revolutionary workflow and process-change around the technology that will help users realize greater benefits. Interestingly, Louis Gerstner Jr., in an interview about his new book, Who Says Elephants Can’t Dance? says (about the computer industry) “. . . the process of integrating this technology and achieving the benefit is unbelievably painful for companies. The industry has been all about faster, faster, more function, more function. . . .” It appears, at least in this regard, that PACS shares the challenges of the rest of the computer industry!

IT HAS BEEN ASTOUNDING to witness the two-decade computing evolution, which increased processing power, communications bandwidth, and storage capacity while reducing costs. Most of the technology limitations that challenged our early development of picture archiving and communications system (PACS) development have been dissolved. Our quest for modular components has been partially facilitated by the developments of DICOM v3 and more recently by the Radiological Society of North America (RSNA) and the Healthcare Information and Management Systems Society (HIMSS) initiative to address the integration of the healthcare environment (IHE). While many of the commercial systems are still limited in their ability to be tailored to support the radiologist’s need for specialized workflow, adoption of the IHE technical framework holds promise. As in the PACS Workbench experiments, we still find it is essential to have tools to measure image flow, queue arrival times, and queue departure times in order to understand the bounds and performance of our installed commercial systems. The dynamic display of performance metrics, missing in many systems today, continues to be required to enable the “measured, scientific approach” that we sought in our original implementations.